Our understanding of the molecular biology of cancer has improved dramatically over the past thirty years, and many potential therapeutic agents have been developed. However, a way to realize the full clinical potential of these agents have been developed. However, a way to realize the full clinical potential of these agents has yet to be found. Our hypothesis is that a therapeutic agent must satisfy two requirements to be effective: (1) the agent must be delivered to the target cells in vivo in optimal quantities, remaining there for an appropriate time at sufficient concentrations, and (2) the agent must be effective in the in vivo microenvironment will significantly improve the delivery and effectiveness of many types of therapeutic agents. This Program Project Grant (PPG) application builds on these premises. Our primary objective is to develop a quantitative understanding of the physiological barriers to the delivery and effectiveness of conventional and novel therapeutic agents used for solid tumor treatment. Our secondary objective is to seek strategies with the potential to overcome these barriers. We will investigate the first barrier associated with blood flow in Project 1, the second barrier associated with transvascular transport in Project 2, the third barrier associated with interstitial transport in Project 3, and the fourth barrier associated with cell delivery in Project 4. By growing the same tumor in different host organs (e.g., brain, liver, subcutaneous tissue), we will delineate the role of tumor-host interactions in each barrier function. Each barrier is unique, requiring its own set of "physiological resistance modifiers." Based on preliminary data we will use VEGF and bFGF to modify the vascular barrier (Projects 1 and 2), relaxin to modify the interstitial barrier (Project 3), and various cytokines to overcome barriers to cell delivery and function (Project 4). A high project relies upon the common in vivo microscopy techniques (Core A), shared cellular and molecular resources (Core B), and common animal models and tumors (Core C), in addition to a standard administrative core (Core D). The interdependent and multi-disciplinary nature of these pro4ejcts and cores make this PPG an integrated whole that is greater than the sum of its parts. Since a quantitative understanding of tumor pathophysiology is vital to realize the fruits of the NIH's investment in the molecular biology of cancer, funding the proposed PPG would fill an urgent need.